Improved endothelialization of small-diameter ePTFE vascular grafts through growth factor therapy

BACKGROUND: Prosthetic vascular grafts in humans characteristically lack confluent endothelialization regardless of the duration of implantation. Use of high-porosity grafts has been proposed as a way to induce endothelialization through transgraft capillarization, although early experiments failed to show increased healing in man. OBJECTIVES: We hypothesized that transduction of tissues around the prosthetic conduit with vectors encoding VEGF receptor-2 (VEGFR2) ligands would augment transinterstitial capillarization and induce luminal endothelialization of high-porosity ePTFE grafts. METHODS: Fifty-two NZW rabbits received 87 ePTFE uni- or bilateral end-to-end interposition grafts in carotid arteries. Rabbits were randomized to local therapy with adenoviruses encoding AdVEGF-A165, AdVEGF-A109 or control AdLacZ and analyzed at 6 and 28 days after surgery by contrast-enhanced ultrasound and histology. RESULTS: AdVEGF-A165 and AdVEGF-A109 dramatically increased perfusion in perigraft tissues at 6 days (14.2 ± 3.6 or 16.7 ± 2.6-fold increases, P < 0.05 and P < 0.01). At 28 days, the effect was no longer significantly higher than baseline. At 6 days, no luminal endothelialization was observed in any of the groups. At 28 days, AdVEGF-A109- and AdVEGF-A165-treated animals showed enhanced ingrowth of transinterstitial capillaries (66.0 ± 13.7% and 77.4 ± 15.7% of graft thickness vs 44.7 ± 24.4% in controls, P < 0.05) and improved luminal endothelialization (11.2 ± 26.3% and 11.4 ± 22.2%, AdVEGF-A109 and AdVEGF-A165 vs 0% in controls, P < 0.05). No increased stenosis was observed in the treatment groups as compared to LacZ controls. CONCLUSIONS: This study suggests that transient local overexpression of VEGFR2 ligands in the peri-implant tissues at the time of graft implantation is a novel strategy to increase endothelialization of high-porosity ePTFE vascular grafts and improve the patency of small-diameter vascular prostheses.